Bone mass is a strong determinant of fracture risk, and recent evidence suggests that bone turnover may also be related to fracture risk. Current FDA approved approaches to osteoporosis consist of estrogens, calcitonin, bisphosphonates, and raloxifene. All reduce bone turnover and result in modest increases in bone mass, presumed to be due primarily to reduction in remodeling space. In many individuals with osteoporosis, these gents do not increase bone mass sufficiently to eliminate fractures, indicating a need for agents that are anabolic to the skeleton. In the past funding period, e showed that hPTH increases bone mass especially in the spine in postmenopausal estrogenized women and may be associated with a reduction in vertebral fracture risk. Mechanistically, PTH, in the presence of an anti-resorptive agent, increases bone formation markers within the first weeks of treatment, while resorption markers increase later, after which both are similarly elevated. Our current proposal seeks to evaluate the mechanism of PTH action on human bone physiology. We propose to define the early skeletal response to PTH which underlies the rapid increase in formation biochemistry and bone mass, using histomorphometry. We will evaluate the importance of the anti-resorptive agent in determining the initial bone response and possibly modifying site specific skeletal responses to PTH. Finally, we will determine the skeletal responses to discontinuation of PTH and subsequent rechallenge to determine if a second anabolic response can be mounted by the skeleton. These studies should allow better definition of appropriate clinical protocols for PTH use, as well as defining the mechanisms underlying the short-term and long-term anabolic actions of PTH in the human.